Project Summary/Abstract Age-related loss of muscle mass and function (sarcopenia) is a major cause of disability, falls and fractures, thus constituting a substantial public health problem. Novel sarcopenia interventions and the tools to identify those who should be treated are needed, yet a major barrier to their development is the limited understanding of sarcopenia risk factors and its underlying physiology. Age-related fat gain may be physiologically linked to sarcopenia, which could substantially impact the health of older adults given the recent obesity epidemic. The long-term goal of this research is to elucidate the role of fat mass and its distribution in the age-related loss of muscle mass and strength, ultimately leading to development of novel interventions for sarcopenia. The primary objective of this R03 project is to determine the association of abdominal fat distribution with muscle mass, strength, strength-to-mass ratio (muscle quality), and physical performance, and whether adipocytokines partly explain these associations. The central hypothesis is that greater visceral and subcutaneous adipose tissue (VAT and SAT) volumes from computed tomography (CT) scans are associated with lower muscle mass, strength, and quality, and with reduced physical performance; further, these associations will be explained, at least in part, by circulating concentrations of adipocytokines. The rationale is that evidence supporting adipocytokines as a link between fat gain and muscle loss could lead to novel sarcopenia therapies that target this pathway. A second objective is to validate SAT measured by dual-energy x-ray absorptiometry (DXA) against CT. The rationale for this objective is that DXA is more readily available than CT, and validating DXA SAT will facilitate expansion of research on fat distribution and sarcopenia. Further, if VAT and SAT predict loss of muscle mass and function, they are potential novel clinical tools for identifying individuals at risk for sarcopenia. Our hypotheses will be tested using previously collected data from the Framingham Offspring and Third Generation (Gen3) Cohorts. Aim 1 will determine, in ~1,400 Offspring men and women, the association of abdominal VAT and SAT, measured by CT, with relative appendicular lean mass, relative quadriceps muscle strength, quadriceps muscle quality, and chair-stand time, and whether these associations are explained by plasma concentrations of the adipocytokines interleukin-6, monocyte chemoattractant protein- 1, adiponectin or resistin. Aim 2 will validate DXA abdominal SAT against CT SAT using data from ~1,400 men and women in the Gen3 cohort. This research is innovative because it will examine the role of fat distribution in age-related decline in muscle health, and it will be the first to validate DXA SAT. The proposed research is significant because it is a crucial step for promoting development of sarcopenia therapies that may regulate the adipocytokines that are detrimental to muscle, and it will progress research that will contribute to improving sarcopenia risk assessment and personalization of sarcopenia interventions. Advancement in these research areas will eventually help reduce the public health and economic burdens of sarcopenia in the U.S.